Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens or allogeneic stem cell transplantation. However, 20-40% of patients without transplant options do not respond to immunosuppressive therapies, and have persistent severe thrombocytopenia. Even patients that respond to immunosuppressive therapies with an improvement in their life-threatening neutropenia sometimes have persistent thrombocytopenia. Both groups of patients (i.e. nonresponders to immunosuppressive therapy and responders with persistent thrombocytopenia) require regular platelet transfusions, which are expensive and inconvenient, and are a risk for further serious bleeding complications.

Thrombopoietin (TPO) is the principal endogenous regulator of platelet production. On binding to the megakaryocyte progenitor TPO receptor, TPO initiates a number of signal transduction events to increase the production of mature megakaryocytes and platelets. Thrombopoietin also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in animal models. A 2nd generation small molecule TPO-agonist, eltrombopag (Promacta ) has been shown to increase platelets in healthy subjects and in thrombocytopenic patients with chronic immune thrombocytopenic purpura (ITP) and hepatitis C virus (HCV) infection. Eltrombopag is administered orally and has been well-tolerated in clinical trials. Unlike recombinant TPO, it has not been found to induce autoantibodies. Eltrombopag received FDA accelerated approval on Nov 20, 2008 for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Because a paucity of megakaryocytes and decreased platelet production is responsible for thrombocytopenia in aplastic anemia patients, we now propose this Phase 2, non-randomized pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy refractory thrombocytopenia.

Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East Asians), which will be increased or decreased as clinically indicated to the lowest dose that maintains a stable platelet count 20,000/(micro)L above baseline while maximizing tolerability. Treatment response is defined as platelet count increases to 20,000/(micro)L above baseline at three months. Subjects with response at 3 months may continue study medication (extended access) until they meet an off study criteria.

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

The portion of drug responders as defined by changes in the platelet count and/or platelet transfusion requirements and the toxicity profile as measured at 12 weeks using the CTCAE criteria. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Incidence of bleeding; changes in serum thrombopoietin level (as measured by enzyme-linked immunosorbent assay, R&amp;D Systems), and health related quality of life (as measured by the Medical Outcomes Study 36-item Short Form General Health...

Diagnosis of aplastic anemia, with refractory thrombocytopenia following at least one treatment course of horse or rabbit ATG/cyclosporine.

Platelet count less than or equal to 30,000/microL

Age greater than or equal to 12 years old

EXCLUSION CRITERIA:

Diagnosis of Fanconi anemia

Infection not adequately responding to appropriate therapy

Patients with a PNH clone size in neutrophils of greater than or equal to 50%

HIV positivity

Creatinine > 2.5

Bilirubin > 2.0

SGOT or SGPT > 5 times the upper limit of normal

Hypersensitivity to eltrombopag or its components

Female subjects who are nursing or pregnant or are unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential

History of malignancy other than localized tumors diagnosed more than one year previously and treated surgically with curative intent (for instance squamous cell or other skin cancers, stage 1 breast cancer, cervical carcinoma in situ, etc)

Unable to understand the investigational nature of the study or give informed consent

History of congestive heart failure arrhythmia requiring chronic treatment, arterial or venous thrombosis (not excluding line thrombosis) within the last 1 year, or myocardial infarction within 3 months before enrollment

ECOG Performance Status of 3 or greater

Treatment with horse or rabbit ATG or Campath within 6 months of study entry. Concurrent stable treatment with cyclosporine or G-CSF is permitted.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00922883